The heart is an innervated multi-chambered muscular organ that maintains blood flow through the circulatory system of the body. In a normal, healthy heart, blood flow is regulated by a coordinated contraction and relaxation of various heart chambers. The coordinated contraction and relaxation is controlled by periodic electrical depolarizations originating from the sino-atrial (SA) node located in the posterior wall of the right atrium. The SA node is a population of specialized cardiac cells that act as a pacemaker by generating cellular depolarizations, termed action potentials, at regular intervals in response to physiological inputs. The SA node is richly innervated by vagal and sympathetic fibers, making it susceptible to autonomic influences. Stimulation of the vagus nerve for instance causes a decrease in the rate of action potentials generated by the SA node, causing a decrease in heart rate. Conversely stimulation via sympathetic fibers causes an increase in the rate of action potential generation, thereby increasing heart rate and blood flow. Action potentials generated by the SA node are conducted throughout the heart in a regulated manner to ensure coordinated contraction and relaxation of the various chambers.
Coordinated depolarization of cardiac tissue should occur in a controlled manner throughout the heart chambers to maintain high pumping efficiency. A depolarization generated by the SA node is initially conducted through the atria, causing the atria to contract and forcing blood from the atria into the ventricles. The depolarization pulse then conducts to the atrio-ventricular (AV) node and onto a group of specialized conducting myocardial cells termed Purkinje fibers, where it is transmitted through the inter-ventricular septum and ventricles. The depolarized left and right ventricles contract, forcing blood out of the heart and through the circulatory system of the body.
Numerous cardiac pathologies may affect the myocardial depolarization process. For example, acute myocardial events, such as a myocardial infarction, may damage cardiac conduction pathways, leading to altered depolarization progression throughout the myocardium that may decrease cardiac output and/or pumping efficiency. Chronic conditions, such as high blood pressure, valvular disease, certain types of infection, and diabetes may give rise to slowly-progressing conduction disturbances and contraction inefficiencies.
Under some circumstances pharmaceutical therapies may partially restore heart function. Many pharmacologic treatments are effective at increasing cardiac output, preventing arrhythmias, and/or treating symptoms associated with heart failure. However, for some patients, pharmaceutical therapy may be ineffective or inadequate. For example, many patients who have suffered acute or chronic damage to myocardial conduction pathways have lasting and/or recurring arrhythmias. In some patients, conduction through the ventricles may be abnormal and/or the depolarizations may be asynchronous, whereby contractions of the atria and ventricles are poorly coordinated. These condition disturbances may have a deleterious effect on cardiac output, may contribute to the progression of cardiac disease, and may ultimately lead to death.
For some patients implantable cardiac rhythm management (CRM) systems may be used to reduce the effects of conduction abnormalities. CRM systems may include pacemakers and/or defibrillators configured to provide electrical stimulation to specific regions of the myocardium. Pacemakers generally include a pulse generator which houses various electrical components, such as a battery, control hardware, communications systems, and/or other diagnostic components. The pacemaker may also include a number of leads and electrodes configured to transmit an electrical stimulation pulse from the pulse generator to specific regions of the myocardium. Numerous different pacemakers, defibrillators, leads and electrodes are available, depending on the pathology to be treated and clinical factors of the patient.
More recently, various biological therapeutics have been proposed to treat various cardiac pathologies, and some are currently undergoing clinical development. These biological therapies include gene-based and cell-based therapies; gene-based therapies aim to modify or supplement endogenous gene expression of existing cardiomyocytes while cell-based therapies includes augmentation or replacement of existing cardiomyocytes with other cells. It is also possible to combine gene-based and cell-based therapies to genetically modify cells prior to transplantation into the heart. Such therapies may also benefit from advances being developed for stem cell therapeutics.
The various molecular mechanisms underlying cardiac functionality are complex. Numerous ion channels are known to regulate specific ion fluxes across the cellular membranes of cardiomyocytes, and various gap junctions have been identified and shown to allow current flow between adjacent cells. Different distributions of various membrane associated proteins and protein complexes are also thought to contribute to various conduction processes within the myocardium. Recent work has also highlighted the heterogeneity of various myocardial cell populations, revealing molecular differences between cells of the SA node, AV node, Purkinje fibers, atrial myocytes, and ventricular myocytes. Such molecular heterogeneity partially contributes to different electrophysiological activity of the various cardiac cell types, and action potential propagation throughout the myocardium.
Improved molecular and cellular techniques may permit formation of cell types with molecular properties that mimic the cellular functions of the various cell populations of the native heart. For example, cells may be genetically altered to upregulate expression of HCN2 and/or HCN4, ion channels associated with a current (termed “funny” current, If) that flows across a cell membrane and leads to the spontaneous depolarization of SA node type cells. Genetically altered cells may be engineered to replace or augment the function of natural cardiac pacemaker cells, such as the SA and AV nodes, and upon implantation may help to restore appropriate generation and/or propagation of action potentials.
The spontaneous rate of depolarization of cardiac cells is dependent on the type and density of various ion channels, local ion concentrations, neurohormonal state and the local transmembrane potential. The kinetics of specific types of ion channels may be dependent upon specific current-voltage relationships as transmembrane potential may influence channel gating. Channels of different sequence and/or conformation may exhibit different current-voltage relationships, and different types of channels may activate, deactivate, and/or maintain a particular state at different potentials. Such regulation of channel gating affects the timing and duration of ion fluxes caused by specific ion channels. In the case of the funny current, altering a cell's transmembrane potential through application of a local field can modify the cell's channel kinetics to alter the cell's rate of spontaneous depolarization.
Effective functioning of cells introduced into the myocardium may benefit from concurrent use of a Cardiac Rhythm Management (CRM) system. For example, the introduced pacemaker cells may initially have a limited pacing rate that may be insufficient during high metabolic demand. The introduced cells may also require a training period whereby the CRM system may pace the introduced cells at specific rates to enhance formation of gap functions and/or other proteins required for adequate engraftment. Further, the introduced cells may be temporarily or permanently affected by medications or other condition that may affect normal myocardial cells (e.g. infarction). In addition, a CRM system may be desired to monitor, record, and/or transmit information related to patient status to healthcare professionals to facilitate continued treatment.
The present disclosure provides systems, devices and methods for providing local field stimulation to affect the transmembrane potential of one or more cells.